title: A genome-wide association study in American Indians implicates DNER as a susceptibility locus for type 2 diabetes.
abstract: Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls, and a family-based association test was conducted. Tag SNPs (n = 311) were selected for 499 SNPs associated with diabetes (P < 0.0005 in case-control analyses or P < 0.0003 in family-based analyses), and these SNPs were genotyped in up to 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10(-8), which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.forename: Yunhua L
authors.initials: YL
authors.lastname: Muller
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.forename: Tingwei
authors.initials: T
authors.lastname: Guo
authors.forename: Li
authors.initials: L
authors.lastname: Bian
authors.forename: Victoria
authors.initials: V
authors.lastname: Ossowski
authors.forename: Kim
authors.initials: K
authors.lastname: Wiedrich
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sutherland
authors.forename: Christopher
authors.initials: C
authors.lastname: Wiedrich
authors.forename: Darin
authors.initials: D
authors.lastname: Mahkee
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Maryam
authors.initials: M
authors.lastname: Abdussamad
authors.forename: Michael
authors.initials: M
authors.lastname: Traurig
authors.forename: E Jennifer
authors.initials: EJ
authors.lastname: Weil
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bennett
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: C462501:DNER protein, human; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface